1qpc Citations

Structural analysis of the lymphocyte-specific kinase Lck in complex with non-selective and Src family selective kinase inhibitors.

Structure 7 651-61 (1999)
Related entries: 1qpd, 1qpe, 1qpj

Cited: 87 times
EuropePMC logo PMID: 10404594

Abstract

Background

The lymphocyte-specific kinase Lck is a member of the Src family of non-receptor tyrosine kinases. Lck catalyzes the initial phosphorylation of T-cell receptor components that is necessary for signal transduction and T-cell activation. On the basis of both biochemical and genetic studies, Lck is considered an attractive cell-specific target for the design of novel T-cell immunosuppressants. To date, the lack of detailed structural information on the mode of inhibitor binding to Lck has limited the discovery of novel Lck inhibitors.

Results

We report here the high-resolution crystal structures of an activated Lck kinase domain in complex with three structurally distinct ATP-competitive inhibitors: AMP-PNP (a non-selective, non-hydrolyzable ATP analog); staurosporine (a potent but non-selective protein kinase inhibitor); and PP2 (a potent Src family selective protein tyrosine kinase inhibitor). Comparison of these structures reveals subtle but important structural changes at the ATP-binding site. Furthermore, PP2 is found to access a deep, hydrophobic pocket near the ATP-binding cleft of the enzyme; this binding pocket is not occupied by either AMP-PNP or staurosporine.

Conclusion

The potency of staurosporine against Lck derives in part from an induced movement of the glycine-rich loop of the enzyme upon binding of this ligand, which maximizes the van der Waals interactions present in the complex. In contrast, PP2 binds tightly and selectively to Lck and other Src family kinases by making additional contacts in a deep, hydrophobic pocket adjacent to the ATP-binding site; the amino acid composition of this pocket is unique to Src family kinases. The structures of these Lck complexes offer useful structural insights as they demonstrate that kinase selectivity can be achieved with small-molecule inhibitors that exploit subtle topological differences among protein kinases.

Articles - 1qpc mentioned but not cited (3)

  1. Activation of tyrosine kinases by mutation of the gatekeeper threonine. Azam M, Seeliger MA, Gray NS, Kuriyan J, Daley GQ. Nat. Struct. Mol. Biol. 15 1109-1118 (2008)
  2. Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. Bartels CF, Bükülmez H, Padayatti P, Rhee DK, van Ravenswaaij-Arts C, Pauli RM, Mundlos S, Chitayat D, Shih LY, Al-Gazali LI, Kant S, Cole T, Morton J, Cormier-Daire V, Faivre L, Lees M, Kirk J, Mortier GR, Leroy J, Zabel B, Kim CA, Crow Y, Braverman NE, van den Akker F, Warman ML. Am. J. Hum. Genet. 75 27-34 (2004)
  3. An aggregate analysis of many predicted structures to reduce errors in protein structure comparison caused by conformational flexibility. Godshall BG, Tang Y, Yang W, Chen BY. BMC Struct. Biol. 13 Suppl 1 S10 (2013)


Reviews citing this publication (15)

  1. Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges. Breen ME, Soellner MB. ACS Chem. Biol. 10 175-189 (2015)
  2. Interleukin-1 receptor associated kinase inhibitors: potential therapeutic agents for inflammatory- and immune-related disorders. Bahia MS, Kaur M, Silakari P, Silakari O. Cell. Signal. 27 1039-1055 (2015)
  3. Update on lymphocyte specific kinase inhibitors: a patent survey. Martin MW, Machacek MR. Expert Opin Ther Pat 20 1573-1593 (2010)
  4. The current status of drug discovery against the human kinome. Eglen RM, Reisine T. Assay Drug Dev Technol 7 22-43 (2009)
  5. IRAK-4 inhibitors for inflammation. Wang Z, Wesche H, Stevens T, Walker N, Yeh WC. Curr Top Med Chem 9 724-737 (2009)
  6. Large crystal growth by thermal control allows combined X-ray and neutron crystallographic studies to elucidate the protonation states in Aspergillus flavus urate oxidase. Oksanen E, Blakeley MP, Bonneté F, Dauvergne MT, Dauvergne F, Budayova-Spano M. J R Soc Interface 6 Suppl 5 S599-610 (2009)
  7. Oxyl radicals, redox-sensitive signalling cascades and antioxidants. Genestra M. Cell. Signal. 19 1807-1819 (2007)
  8. Tyrphostins and other tyrosine kinase inhibitors. Levitzki A, Mishani E. Annu. Rev. Biochem. 75 93-109 (2006)
  9. Structural biology in drug design: selective protein kinase inhibitors. Scapin G. Drug Discov. Today 7 601-611 (2002)
  10. The genesis of high-throughput structure-based drug discovery using protein crystallography. Kuhn P, Wilson K, Patch MG, Stevens RC. Curr Opin Chem Biol 6 704-710 (2002)
  11. Structural aspects of protein kinase control-role of conformational flexibility. Engh RA, Bossemeyer D. Pharmacol. Ther. 93 99-111 (2002)
  12. Magic bullets for protein kinases. Bishop AC, Buzko O, Shokat KM. Trends Cell Biol. 11 167-172 (2001)
  13. ATP site-directed competitive and irreversible inhibitors of protein kinases. García-Echeverría C, Traxler P, Evans DB. Med Res Rev 20 28-57 (2000)
  14. Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia. Druker BJ, Lydon NB. J. Clin. Invest. 105 3-7 (2000)
  15. Protein tyrosine kinase structure and function. Hubbard SR, Till JH. Annu. Rev. Biochem. 69 373-398 (2000)

Articles citing this publication (69)

  1. Structural determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin, and staurosporine. Walker EH, Pacold ME, Perisic O, Stephens L, Hawkins PT, Wymann MP, Williams RL. Mol. Cell 6 909-919 (2000)
  2. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, Eck MJ. Cancer Cell 11 217-227 (2007)
  3. Structural bioinformatics-based design of selective, irreversible kinase inhibitors. Cohen MS, Zhang C, Shokat KM, Taunton J. Science 308 1318-1321 (2005)
  4. Structural basis for the autoinhibition of focal adhesion kinase. Lietha D, Cai X, Ceccarelli DF, Li Y, Schaller MD, Eck MJ. Cell 129 1177-1187 (2007)
  5. Discovery of selective irreversible inhibitors for Bruton's tyrosine kinase. Pan Z, Scheerens H, Li SJ, Schultz BE, Sprengeler PA, Burrill LC, Mendonca RV, Sweeney MD, Scott KC, Grothaus PG, Jeffery DA, Spoerke JM, Honigberg LA, Young PR, Dalrymple SA, Palmer JT. ChemMedChem 2 58-61 (2007)
  6. Structural basis for selective inhibition of Src family kinases by PP1. Liu Y, Bishop A, Witucki L, Kraybill B, Shimizu E, Tsien J, Ubersax J, Blethrow J, Morgan DO, Shokat KM. Chem. Biol. 6 671-678 (1999)
  7. Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors. Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M. J. Mol. Biol. 333 393-407 (2003)
  8. IL-2 negatively regulates IL-7 receptor alpha chain expression in activated T lymphocytes. Xue HH, Kovanen PE, Pise-Masison CA, Berg M, Radovich MF, Brady JN, Leonard WJ. Proc. Natl. Acad. Sci. U.S.A. 99 13759-13764 (2002)
  9. Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Boggon TJ, Li Y, Manley PW, Eck MJ. Blood 106 996-1002 (2005)
  10. Unexpected effects of FERM domain mutations on catalytic activity of Jak3: structural implication for Janus kinases. Zhou YJ, Chen M, Cusack NA, Kimmel LH, Magnuson KS, Boyd JG, Lin W, Roberts JL, Lengi A, Buckley RH, Geahlen RL, Candotti F, Gadina M, Changelian PS, O'Shea JJ. Mol. Cell 8 959-969 (2001)
  11. 3-Anilino-4-arylmaleimides: potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). Smith DG, Buffet M, Fenwick AE, Haigh D, Ife RJ, Saunders M, Slingsby BP, Stacey R, Ward RW. Bioorg. Med. Chem. Lett. 11 635-639 (2001)
  12. Crystal structures of IRAK-4 kinase in complex with inhibitors: a serine/threonine kinase with tyrosine as a gatekeeper. Wang Z, Liu J, Sudom A, Ayres M, Li S, Wesche H, Powers JP, Walker NP. Structure 14 1835-1844 (2006)
  13. Proteome-wide identification of cellular targets affected by bisindolylmaleimide-type protein kinase C inhibitors. Brehmer D, Godl K, Zech B, Wissing J, Daub H. Mol. Cell Proteomics 3 490-500 (2004)
  14. Structural basis for the recognition of c-Src by its inactivator Csk. Levinson NM, Seeliger MA, Cole PA, Kuriyan J. Cell 134 124-134 (2008)
  15. The structure of JNK3 in complex with small molecule inhibitors: structural basis for potency and selectivity. Scapin G, Patel SB, Lisnock J, Becker JW, LoGrasso PV. Chem. Biol. 10 705-712 (2003)
  16. Insights into regulation of human Schwann cell proliferation by Erk1/2 via a MEK-independent and p56Lck-dependent pathway from leprosy bacilli. Tapinos N, Rambukkana A. Proc. Natl. Acad. Sci. U.S.A. 102 9188-9193 (2005)
  17. Structural basis for UCN-01 (7-hydroxystaurosporine) specificity and PDK1 (3-phosphoinositide-dependent protein kinase-1) inhibition. Komander D, Kular GS, Bain J, Elliott M, Alessi DR, Van Aalten DM. Biochem. J. 375 255-262 (2003)
  18. Trafficking of Lyn through the Golgi caveolin involves the charged residues on alphaE and alphaI helices in the kinase domain. Kasahara K, Nakayama Y, Ikeda K, Fukushima Y, Matsuda D, Horimoto S, Yamaguchi N. J. Cell Biol. 165 641-652 (2004)
  19. Stretch of beta 1 integrin activates an outwardly rectifying chloride current via FAK and Src in rabbit ventricular myocytes. Browe DM, Baumgarten CM. J. Gen. Physiol. 122 689-702 (2003)
  20. The pp60c-Src inhibitor PP1 is non-competitive against ATP. Karni R, Mizrachi S, Reiss-Sklan E, Gazit A, Livnah O, Levitzki A. FEBS Lett. 537 47-52 (2003)
  21. A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera. Davies TG, Verdonk ML, Graham B, Saalau-Bethell S, Hamlett CC, McHardy T, Collins I, Garrett MD, Workman P, Woodhead SJ, Jhoti H, Barford D. J. Mol. Biol. 367 882-894 (2007)
  22. Structural and functional characterization of the human protein kinase ASK1. Bunkoczi G, Salah E, Filippakopoulos P, Fedorov O, Müller S, Sobott F, Parker SA, Zhang H, Min W, Turk BE, Knapp S. Structure 15 1215-1226 (2007)
  23. Src kinase activation: A switched electrostatic network. Ozkirimli E, Post CB. Protein Sci. 15 1051-1062 (2006)
  24. Classifying protein kinase structures guides use of ligand-selectivity profiles to predict inactive conformations: structure of lck/imatinib complex. Jacobs MD, Caron PR, Hare BJ. Proteins 70 1451-1460 (2008)
  25. Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck I. Arnold LD, Calderwood DJ, Dixon RW, Johnston DN, Kamens JS, Munschauer R, Rafferty P, Ratnofsky SE. Bioorg. Med. Chem. Lett. 10 2167-2170 (2000)
  26. Crystal structures of active SRC kinase domain complexes. Breitenlechner CB, Kairies NA, Honold K, Scheiblich S, Koll H, Greiter E, Koch S, Schäfer W, Huber R, Engh RA. J. Mol. Biol. 353 222-231 (2005)
  27. Conformational transitions upon ligand binding: holo-structure prediction from apo conformations. Seeliger D, de Groot BL. PLoS Comput. Biol. 6 e1000634 (2010)
  28. Alternative binding modes of an inhibitor to two different kinases. De Moliner E, Brown NR, Johnson LN. Eur. J. Biochem. 270 3174-3181 (2003)
  29. Which electrospray-based ionization method best reflects protein-ligand interactions found in solution? a comparison of ESI, nanoESI, and ESSI for the determination of dissociation constants with mass spectrometry. Jecklin MC, Touboul D, Bovet C, Wortmann A, Zenobi R. J. Am. Soc. Mass Spectrom. 19 332-343 (2008)
  30. Discovery of 2-amino-heteroaryl-benzothiazole-6-anilides as potent p56(lck) inhibitors. Das J, Moquin RV, Lin J, Liu C, Doweyko AM, DeFex HF, Fang Q, Pang S, Pitt S, Shen DR, Schieven GL, Barrish JC, Wityak J. Bioorg. Med. Chem. Lett. 13 2587-2590 (2003)
  31. Structural basis of Src tyrosine kinase inhibition with a new class of potent and selective trisubstituted purine-based compounds. Dalgarno D, Stehle T, Narula S, Schelling P, van Schravendijk MR, Adams S, Andrade L, Keats J, Ram M, Jin L, Grossman T, MacNeil I, Metcalf C, Shakespeare W, Wang Y, Keenan T, Sundaramoorthi R, Bohacek R, Weigele M, Sawyer T. Chem Biol Drug Des 67 46-57 (2006)
  32. Sequence and structural analysis of kinase ATP pocket residues. Vulpetti A, Bosotti R. Farmaco 59 759-765 (2004)
  33. Regulation of the Src family kinase Lck by Hsp90 and ubiquitination. Giannini A, Bijlmakers MJ. Mol. Cell. Biol. 24 5667-5676 (2004)
  34. Mutations of FLT3/ITD confer resistance to multiple tyrosine kinase inhibitors. Williams AB, Nguyen B, Li L, Brown P, Levis M, Leahy D, Small D. Leukemia 27 48-55 (2013)
  35. Can MM-PBSA calculations predict the specificities of protein kinase inhibitors? Page CS, Bates PA. J Comput Chem 27 1990-2007 (2006)
  36. Pyrrolo[2,3-d]pyrimidines containing an extended 5-substituent as potent and selective inhibitors of lck II. Burchat AF, Calderwood DJ, Hirst GC, Holman NJ, Johnston DN, Munschauer R, Rafferty P, Tometzki GB. Bioorg. Med. Chem. Lett. 10 2171-2174 (2000)
  37. Tricyclic quinoxalines as potent kinase inhibitors of PDGFR kinase, Flt3 and Kit. Gazit A, Yee K, Uecker A, Böhmer FD, Sjöblom T, Ostman A, Waltenberger J, Golomb G, Banai S, Heinrich MC, Levitzki A. Bioorg. Med. Chem. 11 2007-2018 (2003)
  38. Src is a major signaling component for CTGF induction by TGF-beta1 in osteoblasts. Zhang X, Arnott JA, Rehman S, Delong WG, Sanjay A, Safadi FF, Popoff SN. J. Cell. Physiol. 224 691-701 (2010)
  39. Identification of a new chemical class of potent angiogenesis inhibitors based on conformational considerations and database searching. Furet P, Bold G, Hofmann F, Manley P, Meyer T, Altmann KH. Bioorg. Med. Chem. Lett. 13 2967-2971 (2003)
  40. Synthesis and biological evaluation of novel macrocyclic bis-7-azaindolylmaleimides as potent and highly selective glycogen synthase kinase-3 beta (GSK-3 beta) inhibitors. Shen L, Prouty C, Conway BR, Westover L, Xu JZ, Look RA, Chen X, Beavers MP, Roberts J, Murray WV, Demarest KT, Kuo GH. Bioorg. Med. Chem. 12 1239-1255 (2004)
  41. Disruption of the EGFR E884-R958 ion pair conserved in the human kinome differentially alters signaling and inhibitor sensitivity. Tang Z, Jiang S, Du R, Petri ET, El-Telbany A, Chan PS, Kijima T, Dietrich S, Matsui K, Kobayashi M, Sasada S, Okamoto N, Suzuki H, Kawahara K, Iwasaki T, Nakagawa K, Kawase I, Christensen JG, Hirashima T, Halmos B, Salgia R, Boggon TJ, Kern JA, Ma PC. Oncogene 28 518-533 (2009)
  42. Discovery of novel 2-(aminoheteroaryl)-thiazole-5-carboxamides as potent and orally active Src-family kinase p56(Lck) inhibitors. Chen P, Norris D, Das J, Spergel SH, Wityak J, Leith L, Zhao R, Chen BC, Pitt S, Pang S, Shen DR, Zhang R, De Fex HF, Doweyko AM, McIntyre KW, Shuster DJ, Behnia K, Schieven GL, Barrish JC. Bioorg. Med. Chem. Lett. 14 6061-6066 (2004)
  43. Development of a HTRF kinase assay for determination of Syk activity. Harbert C, Marshall J, Soh S, Steger K. Curr Chem Genomics 1 20-26 (2008)
  44. Cell permeability as a parameter for lead generation in the protein Tyrosine kinase inhibition field. Papageorgiou C, Camenisch G, Borer X. Bioorg. Med. Chem. Lett. 11 1549-1552 (2001)
  45. Phosphorylation of human enhancer of filamentation (HEF1) on serine 369 induces its proteasomal degradation. Hivert V, Pierre J, Raingeaud J. Biochem. Pharmacol. 78 1017-1025 (2009)
  46. Genistein and tyrphostin AG556 inhibit inwardly-rectifying Kir2.1 channels expressed in HEK 293 cells via protein tyrosine kinase inhibition. Zhang DY, Wu W, Deng XL, Lau CP, Li GR. Biochim. Biophys. Acta 1808 1993-1999 (2011)
  47. Structure determination of human Lck unique and SH3 domains by nuclear magnetic resonance spectroscopy. Briese L, Willbold D. BMC Struct. Biol. 3 3 (2003)
  48. Aurora-A recruitment and centrosomal maturation are regulated by a Golgi-activated pool of Src during G2. Barretta ML, Spano D, D'Ambrosio C, Cervigni RI, Scaloni A, Corda D, Colanzi A. Nat Commun 7 11727 (2016)
  49. The role of Src kinase in the biology and pathogenesis of Acanthamoeba castellanii. Siddiqui R, Iqbal J, Maugueret MJ, Khan NA. Parasit Vectors 5 112 (2012)
  50. The development of novel 1,2-dihydro-pyrimido[4,5-c]pyridazine based inhibitors of lymphocyte specific kinase (Lck). Sabat M, Vanrens JC, Brugel TA, Maier J, Laufersweiler MJ, Golebiowski A, De B, Easwaran V, Hsieh LC, Rosegen J, Berberich S, Suchanek E, Janusz MJ. Bioorg. Med. Chem. Lett. 16 4257-4261 (2006)
  51. Synthesis and activity of novel 5-substituted pyrrolo[2,3-d]pyrimidine analogues as pp60(c-Src) tyrosine kinase inhibitors. Olgen S, Isgör YG, Coban T. Arch. Pharm. (Weinheim) 341 113-120 (2008)
  52. Identifying three-dimensional structures of autophosphorylation complexes in crystals of protein kinases. Xu Q, Malecka KL, Fink L, Jordan EJ, Duffy E, Kolander S, Peterson JR, Dunbrack RL. Sci Signal 8 rs13 (2015)
  53. S1PR1 Tyr143 phosphorylation downregulates endothelial cell surface S1PR1 expression and responsiveness. Chavez A, Schmidt TT, Yazbeck P, Rajput C, Desai B, Sukriti S, Giantsos-Adams K, Knezevic N, Malik AB, Mehta D. J. Cell. Sci. 128 878-887 (2015)
  54. Synthesis, biological evaluation and docking studies of new pyrrolo[2,3-d] pyrimidine derivatives as Src family-selective tyrosine kinase inhibitors. Dincer S, Cetin KT, Onay-Besikci A, Ölgen S. J Enzyme Inhib Med Chem 28 1080-1087 (2013)
  55. Crystal structure of the MAP3K TAO2 kinase domain bound by an inhibitor staurosporine. Zhou TJ, Sun LG, Gao Y, Goldsmith EJ. Acta Biochim. Biophys. Sin. (Shanghai) 38 385-392 (2006)
  56. Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation. Munoz L, Kavanagh ME, Phoa AF, Heng B, Dzamko N, Chen EJ, Doddareddy MR, Guillemin GJ, Kassiou M. Eur J Med Chem 95 29-34 (2015)
  57. One-pot regioselective synthesis of tetrahydroindazolones and evaluation of their antiproliferative and Src kinase inhibitory activities. Rao VK, Chhikara BS, Tiwari R, Shirazi AN, Parang K, Kumar A. Bioorg. Med. Chem. Lett. 22 410-414 (2012)
  58. Evaluation of new indole and bromoindole derivatives as pp60(c-Src) tyrosine kinase inhibitors. Kiliç Z, Işgör YG, Olgen S. Chem Biol Drug Des 74 397-404 (2009)
  59. Molecular docking guided 3D-QSAR CoMFA analysis of N-4-Pyrimidinyl-1H-indazol-4-amine inhibitors of leukocyte-specific protein tyrosine kinase. Awale M, Mohan CG. J Mol Model 14 937-947 (2008)
  60. Structure activity relationships of quinoxalin-2-one derivatives as platelet-derived growth factor-beta receptor (PDGFbeta R) inhibitors, derived from molecular modeling. Mori Y, Hirokawa T, Aoki K, Satomi H, Takeda S, Aburada M, Miyamoto K. Chem. Pharm. Bull. 56 682-687 (2008)
  61. Synthesis and pp60c-Src tyrosine kinase inhibitory activities of novel indole-3-imine and amine derivatives substituted at N1 and C5. Kiliç Z, Isgör YG, Olgen S. Arch. Pharm. (Weinheim) 342 333-343 (2009)
  62. Configurational stability of bisindolylmaleimide cyclophanes: from conformers to the first configurationally stable, atropisomeric bisindolylmaleimides. Barrett S, Bartlett S, Bolt A, Ironmonger A, Joce C, Nelson A, Woodhall T. Chemistry 11 6277-6285 (2005)
  63. Comparison of some 3-(substituted-benzylidene)-1,3-dihydroindolin derivatives as ligands of tyrosine kinase based on binding mode studies and biological assay. Olgen S. Arch. Pharm. Res. 29 1006-1017 (2006)
  64. Structural basis for the inhibitor recognition of human Lyn kinase domain. Miyano N, Kinoshita T, Nakai R, Kirii Y, Yokota K, Tada T. Bioorg. Med. Chem. Lett. 19 6557-6560 (2009)
  65. A novel member of lymphocyte-specific protein tyrosine kinase protein identified in lamprey, Lampetra japonica. Han Y, Liu X, Dai P, Zhao C, Li T, Wang J, Xiao R, Li Q. Acta Biochim. Biophys. Sin. (Shanghai) 46 820-825 (2014)
  66. Auto-thiophosphorylation activity of Src tyrosine kinase. Cabail MZ, Chen EI, Koller A, Miller WT. BMC Biochem. 17 13 (2016)
  67. An electrostatic selection mechanism controls sequential kinase signaling downstream of the T cell receptor. Shah NH, Wang Q, Yan Q, Karandur D, Kadlecek TA, Fallahee IR, Russ WP, Ranganathan R, Weiss A, Kuriyan J. Elife 5 (2016)
  68. 3D structural analysis of protein O-mannosyl kinase, POMK, a causative gene product of dystroglycanopathy. Nagae M, Mishra SK, Neyazaki M, Oi R, Ikeda A, Matsugaki N, Akashi S, Manya H, Mizuno M, Yagi H, Kato K, Senda T, Endo T, Nogi T, Yamaguchi Y. Genes Cells 22 348-359 (2017)
  69. ROS-dependent activation of RhoA/Rho-kinase in pulmonary artery: Role of Src-family kinases and ARHGEF1. MacKay CE, Shaifta Y, Snetkov VV, Francois AA, Ward JPT, Knock GA. Free Radic. Biol. Med. 110 316-331 (2017)